Carcinogenicity testing is essential to identify hazards associated with exposures to agents, chemicals, or pharmaceuticals. These carcinogenicity hazard identification approaches have progressed from purely epidemiological observations to lifetime rodent bioassays complemented by a variety of in vitro approaches. However, with an increased emphasis on the replace, reduce, refine principle, there is a push to develop assays that have higher throughput and also have reduced or no animal studies. This article reviews the evolution of the carcinogenicity testing from the past century to the current and potential future approaches. These newer approaches leverage existing information, generate data from high-throughput screening methods, and toxicogenomic advances to provide preliminary data on the carcinogenic hazard posed by the respective compounds. These approaches can help in the prioritization of chemicals for rodent bioassays and in some cases potentially obviate the need for carcinogenicity testing in rodents. In summary, in the future, multiple streams of data from numerous in vitro and short-term animal studies can potentially help in identifying carcinogenic hazards without conducting the rodent cancer bioassays, but they may not be able to supplant them entirely.

The ACVP’s mission and vision include ‘‘fostering excellence in veterinary pathology’’ and ‘‘to be...the leading force in comparative medical knowledge.’’ The editorial staff ofVeterinary Pathology have been debating whether the one-animal case report contributes to this mission or belongs in the ACVP’s journal. Editorial staff members are unified in their belief that Veterinary Pathology should include case reports, but should not be seen as a ‘‘case-report’’ journal. The Instructions to Authors specifically establish the expectation that a case report ‘‘provide a unique or outstanding pathologic description of general interest to Veterinary Pathology readers; it is not sufficient to be the first report of an entity in one species...’’ So, who are the readers of Veterinary Pathology? Diagnostic pathologists read Veterinary Pathology and seek case reports when they encounter a seemingly new entity. Toxicologic pathologists rely on case reports to support the classification of a rare lesion as spontaneous and to distinguish it from one induced by a study compound. Pathology residents read Veterinary Pathology, including the case reports, and a resident’s first publication is often based on a diagnostic case. However, all authors should consider reporting a case series or retrospective study (rather than a one-animal case report) to increase the value of their publications (for themselves, for the readership, and for the Journal ). Interestingly, a one-animal case report tops the list of the 50 most-frequently-read articles for October 2007 (based on hits at www.vetpathology.org). Nevertheless, one-animal case reports appear only 6 more times in the list and not at all in the November 2007 list of most-frequently-cited articles. The best case reports are derived from novel disease presentations and well-documented diagnostic investigations that challenge current dogma. The value of these reports is acknowledged, and they will continue to be welcomed by the editorial staff. On the other hand, case reports of classical presentations of well-recognized diseases should not be published in Veterinary Pathology because they do not provide unique information. Nonetheless, many of these studies have intrinsic educational value, so the editorial staff has debated how to disseminate that instructive information. To bring these case reports to all pathologists and pathologists-in-training, the editors are considering a Diagnostic Challenge section in Veterinary Pathology and the possibility of publishing certain case reports online in lieu of in the printed journal. In addition, because some case reports that do not meet Veterinary Pathology’s publication criteria have educational value and appeal for veterinary students or practitioners with an interest in pathology, the ACVP will launch a regular feature article in the Veterinary Medicine Today section of the Journal of the American Veterinary Medical Association in 2008. Veterinary Pathology still needs case reports and the editors want the journal to be the first choice for authors of case reports that contain new information or challenge current dogma. To advance the journal’s standing among comparative medical publications and to maintain its high standards, the length and number of case reports may be limited to increase space for other articles. Simultaneously, we are seeking alternative ways to distribute classical case report information to the veterinary pathology community. We encourage additional viewpoints from the readership and will provide a forum for these in a ‘‘Letter to the Editor’’ (vetpath@nc.rr.com). Vet Pathol 45:123 (2008)

The purpose of this study was to evaluate the toxicity and potential carcinogenicity or cocarcinogenicity of ozone exposure in rats. Fischer-344/N (F-344/N) rats were exposed 6 hr/day, 5 days/wk, to 0, 0.12, 0.5, or 1.0 ppm ozone by inhalation for 2-yr and lifetime exposures. The cocarcinogenicity study included subcutaneous administration of 0, 0.1, or 1.0 mg/kg body weight of 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and inhalation of 0 or 0.5 ppm ozone to male rats. NNK was administered by subcutaneous injections 3 times per week for the first 20 wk with ozone inhalation exposure. The ozone inhalation exposure was for 2 yr (104 wk), including the first 20 wk of NNK treatment and continuing for 84 wk after the last NNK injection. Ozone exposure caused a concentration-related increase in inflammation of the centriacinar region of the lung. There was also increased fibrosis and an extension of the bronchiolar epithelium in these centriacinar regions to involve the proximal alveoli. There was no increased incidence of neoplasms at any site, including the lung, that was associated with ozone exposure. Rats administered 1.0 mg/kg body weight NNK alone had an increased incidence of bronchiolar/alveolar neoplasms, but this effect was not enhanced by ozone exposure. Ozone exposure for 2 yr and lifetime was associated with site-specific toxic alterations in the nasal passage and lung similar to those previously described for short-term exposures. While there was significant attenuation of the pulmonary lesions as compared to short-term exposures, lesions persisted in the lifetime study and there was evidence of a mild progressive fibrosis. We conclude that under the conditions of these studies: (a) ozone exposure is not carcinogenic to either male or female F-344/N rats, (b) ozone does not enhance the incidence of pulmonary neoplasms in F-344/N rats exposed to a known pulmonary carcinogen (NNK), and (c) mild site-specific toxic lesions characteristic of ozone exposure persist in the nasal passage and lung throughout the lifetime of the rat with continued ozone exposure.